bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–04–05
ten papers selected by
Susan Logue, University of Manitoba
  1. A neuropeptide regulates cell non-autonomous protein homeostasis.
  2. TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson's disease.
  3. PABPC1-induced stabilization of PGK1 mRNA reduces apoptosis and sunitinib sensitivity in renal cell carcinoma by suppressing endoplasmic reticulum stress.
  4. REDD1/DDIT4 counteracts endoplasmic reticulum stress-induced apoptosis by controlling the expression of death receptor TRAILR2/DR5 in cancer cells.
  5. ATF6 ameliorates renal warm ischemia-reperfusion injury through FHL2-mediated NF-κB signaling pathway.
  6. SEC61: a potential therapeutic target in transplantation.
  7. RNase L Regulates Antiviral Responsiveness through Cleavage of XBP1 mRNA.
  8. Synergistic degradation of circular RNAs by RNAseK and lysosome.
  9. Unexpected role of the integrated stress response in cancer immune evasion.
  10. STING is the scaffold protein for stress granule pre-condensation at the ER.
  1. Cell Rep. 2026 Mar 30. pii: S2211-1247(26)00285-8. [Epub ahead of print]45(4): 117207
    A neuropeptide regulates cell non-autonomous protein homeostasis.
    Carrie A Sheeler, Jacqueline Y Lo, Areebah Rahman, Saebom Kwon, Daviana Menendez Escalera, Emmett Griffin-Baldwin, Karmen Mah, Adam Roszczyk, Jennifer L Garrison, Ashley E Frakes.
      The coordination of proteostasis between the brain and peripheral tissues is essential for the health and survival of all animals. In C. elegans, glia coordinate organismal proteostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPRER). However, the signaling molecules required remain unknown. Here, we show that glial UPRER activation increases levels of specific neuropeptides. We identify a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPRER and protect against chronic ER stress. FLP-17 signals partially through the receptor, EGL-6, to activate transcellular UPRER and confer stress resistance. Both XBP-1 and PERK are required for maximal FLP-17-induced UPRER activation, though only XBP-1 is necessary for organismal ER stress resistance. This work reveals a complex neuropeptide network initiated by glial UPRER activation and identifies FLP-17 as a critical mediator that coopts an existing sensory-metabolic circuit to coordinate organismal proteostasis.
    Keywords:  C. elegans; CP: cell biology; ER stress; cell non-autonomous cellular signaling; cellular stress responses; endoplasmic reticulum; glia; neurons; neuropeptides; protein homeostasis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2026.117207
  2. Cell Death Dis. 2026 Apr 03.
    TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson's disease.
    Pablo Ahumada-Montalva, Francisco Muñoz-Carvajal, Sara Bórquez-Macaya, Nohela Arévalo-Ramírez, Marisol Cisternas-Olmedo, Carolina Jerez, Valentina Urbina-Muñoz, Wileidy Gomez, Pamela J Urrutia, Etienne C Hirsch, Manuel Ahumada, Pablo Barrias, Camila Muñoz-Yañez, Ariel Herrera-Vásquez, Gloria Arriagada, Ute Woehlbier, Melissa Calegaro-Nassif, Mario Sanhueza, Rene L Vidal, Diego Rojas-Rivera.
      The core pathological hallmark of Parkinson's disease (PD) is the progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), driven by misfolding and aggregation of a-synuclein (aSyn) into Lewy bodies. This triggers severe cellular dysfunction, including endoplasmic reticulum (ER) stress and the dysregulation of the unfolded protein response (UPR). TMBIM6, an anti-apoptotic ER protein, inhibits the UPR sensor IRE1a. Although TMBIM6 exhibits neuroprotective effects in neurological disorders, its role in PD-related DAergic neuron survival remains unknown. We report that TMBIM6 mRNA is increased in cellular models exposed to 6-hydroxydopamine (6-OHDA), rotenone, or aSyn preformed fibrils (PFFs), whereas TMBIM6 protein levels are elevated in postmortem PD SNpc, indicating translational relevance. Modulating TMBIM6 expression in DAergic cells and primary neurons showed that knockdown increased aSyn toxicity, while overexpression is protective. Single-cell RNA-seq analysis of PD SN revealed selective disruption of TMBIM6 co-expression with key UPR effectors (HSPA5, ERN1, and XBP1), and reduced TMBIM6 levels in vulnerable DAergic neurons. Mechanistically, TMBIM6 directly binds IRE1a, and aSyn PFFs disrupt this complex, leading to IRE1a activation; genetic or pharmacological IRE1a inhibition prevented cell death in TMBIM6-deficient cells. In vivo, TMBIM6 downregulation in Drosophila melanogaster worsens rotenone-induced DAergic neuron degeneration and motor impairments, while adeno-associated virus (AAV)-mediated TMBIM6 overexpression in mice improves motor function and neuron survival. Our results demonstrate that TMBIM6 modulates ER stress responses, promoting DAergic neuron survival by regulating IRE1a activity. Consequently, the TMBIM6/IRE1a axis represents a promising therapeutic target for mitigating neurodegeneration in PD and related disorders.
    DOI:  https://doi.org/10.1038/s41419-025-08391-5
  3. Cell Death Dis. 2026 Apr 03.
    PABPC1-induced stabilization of PGK1 mRNA reduces apoptosis and sunitinib sensitivity in renal cell carcinoma by suppressing endoplasmic reticulum stress.
    Xinran Chen, Senming Cao, Tongyu Jia, Changwei Shi, Zhenze Yang, Qiyang Liang, Xu Zhang, Liangyou Gu, Xin Ma, Qingbo Huang, Xiubin Li.
      Sunitinib resistance poses a significant challenge in the management of advanced and metastatic clear cell renal cell carcinoma (ccRCC). Although RNA-binding proteins (RBPs) have recently emerged as important regulators of tumorigenesis, their roles in ccRCC progression and sunitinib resistance remain poorly understood. Through comprehensive bioinformatics analysis of clinical datasets, we identified PABPC1 as an RBP significantly upregulated in ccRCC. Functionally, PABPC1 promoted the proliferation, migration, invasion, and sunitinib resistance of ccRCC cells. Mechanistically, PABPC1 bound to and stabilized PGK1 mRNA, thereby upregulating PGK1 expression. This upregulation reduced endoplasmic reticulum (ER) stress, inhibited apoptosis, and consequently conferred sunitinib resistance in ccRCC cells. Importantly, treatment with Eeyarestatin I, a small-molecule ER stress agonist, restored sunitinib sensitivity in tumor cells. These findings reveal a novel PABPC1-PGK1 regulatory axis underlying sunitinib resistance and suggest a promising therapeutic strategy for overcoming drug resistance in ccRCC.
    DOI:  https://doi.org/10.1038/s41419-026-08676-3
  4. Cell Death Dis. 2026 Mar 28.
    REDD1/DDIT4 counteracts endoplasmic reticulum stress-induced apoptosis by controlling the expression of death receptor TRAILR2/DR5 in cancer cells.
    Rocío Mora-Molina, Younes El Yousfi, Cathrin Hagenlocher, Francisco Javier Fernández-Farrán, Markus Rehm, Carmen Palacios, Maria A Christophorou, Abelardo López-Rivas.
      Regulated in development and DNA damage response-1 (REDD1/DDIT4) is induced in response to environmental stress to restrain the mechanistic target of rapamycin complex 1 (mTORC1) signaling as an adaptive strategy to restore cellular homeostasis. Interestingly, REDD1/DDIT4 expression is upregulated in several tumor types including colorectal cancer, suggesting it may have a role in tumourigenesis. Here, we report that activating transcription factor 4 (ATF4)-dependent REDD1/DDIT4 expression is required for survival of colon tumor cells undergoing endoplasmic reticulum (ER) stress through the modulation of TRAILR2/DR5 gene expression. Our findings further demonstrate that resistance to ER stress-induced apoptosis in multicellular tumor spheroids (MCTS) is associated with constitutive expression of REDD1/DDIT4 and diminished mTORC1 activity. CRISPR/Cas9-mediated deletion of REDD1/DDIT4 markedly increases TRAILR2/DR5 expression and enhances apoptosis in spheroids exposed to ER stress. Interestingly, RNA sequencing analysis reveals that the loss of the transcriptional regulator EVI-1/MECOM in cells deficient in REDD1/DDIT4 amplifies the ER stress-induced upregulation of TRAILR2/DR5, leading to enhanced apoptosis. In summary, our findings underscore the crucial role of REDD1/DDIT4 in regulating TRAILR2/DR5-induced caspase-8 activation and apoptosis under chronic ER stress, by inhibiting mTORC1 activity and promoting EVI-1/MECOM-mediated suppression of TRAILR2/DR5 gene expression.
    DOI:  https://doi.org/10.1038/s41419-026-08648-7
  5. iScience. 2026 Apr 17. 29(4): 115173
    ATF6 ameliorates renal warm ischemia-reperfusion injury through FHL2-mediated NF-κB signaling pathway.
    Xuan Wu, Ji-Hua Shi, Yang Bai, Dong-Jing Yang, Meng-Yao Jia, Dan-Feng Guo, Jia-Kai Zhang, Xiao-Yi Shi, Hua-Peng Zhang, Wen-Zhi Guo, Shui-Jun Zhang.
      Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury and transplant dysfunction, involving endoplasmic reticulum stress. Although activating transcription factor 6 (ATF6) regulates ER stress resolution through the unfolded protein response, its specific role in renal I/R injury remains undefined. Here, we employed murine models of renal I/R and cellular hypoxia/reoxygenation (H/R) models to systematically investigate ATF6's function. Our results show that I/R injury significantly upregulates ATF6 expression, particularly in proximal tubular epithelial cells. Functionally, ATF6 activation improved renal function and attenuated inflammation, whereas its inhibition exacerbated tubular damage. Mechanistically, we demonstrated that ATF6 transcriptionally represses four and a half LIM domain protein 2 (FHL2) through direct promoter binding. FHL2, in turn, interacts with TRAF6 to activate the nuclear factor kappa-B (NF-κB) pathway. ATF6 overexpression effectively counteracted FHL2-mediated NF-κB hyperactivation, establishing a protective ATF6/FHL2/NF-κB axis. These findings identify ATF6 as a key renoprotective factor and reveal mechanistic avenues for potential therapies targeting renal I/R injury and transplant complications.
    Keywords:  molecular biology; physiology
    DOI:  https://doi.org/10.1016/j.isci.2026.115173
  6. Front Immunol. 2026 ;17 1787920
    SEC61: a potential therapeutic target in transplantation.
    Maria Laura Saiz, Cristian Ruiz Bernet, Carlos Lopez-Larrea, Beatriz Suarez-Alvarez.
      The SEC61 translocon complex has emerged as a multifunctional therapeutic target linking protein secretion, calcium homeostasis, and immune regulation in kidney transplantation. Beyond canonical protein translocation, SEC61 regulates antigen cross-presentation, cytokine secretion (IL-2, IFN-γ, TNF-α), surface activation molecules (CD62L), and functions as an endoplasmic reticulum calcium-leak channel that modulates unfolded protein response activation under specific physiological and stress conditions. During ischemia-reperfusion injury, ATP depletion impairs SERCA-mediated calcium reuptake while SEC61-mediated calcium efflux persists, triggering ER stress and tubular injury. Selective pharmacological SEC61 inhibition has been proposed to confer multiple immunomodulatory and cytoprotective effects - including reduced antigen cross-presentation, suppression of high-burden secretory lymphocytes, limited T cell migration, and intrinsic antiviral activity through blockade of envelope glycoprotein biogenesis-based on mechanistic and preclinical evidence, although these effects remain to be validated in transplant-specific models. Emerging phase I oncology data with client-selective inhibitors demonstrate the feasibility of pharmacologic SEC61 modulation in humans, although the safety, dosing, and patient population in transplantation may differ substantially from oncology settings. This review examines SEC61's multifaceted roles in transplant immunobiology and its therapeutic potential as a novel immunomodulatory target in kidney transplantation.
    Keywords:  ER proteostasis; ER stress; Sec61; alloimmunity; immunosuppression; ischemia–reperfusion injury; kidney transplantation; translocon
    DOI:  https://doi.org/10.3389/fimmu.2026.1787920
  7. bioRxiv. 2026 Mar 23. pii: 2026.03.21.713401. [Epub ahead of print]
    RNase L Regulates Antiviral Responsiveness through Cleavage of XBP1 mRNA.
    Yoshika Takenaka, Yasutoshi Akiyama, Tsubasa Inaba, Daiki Shinozuka, Katsuki Aoyama, Ransu Ogasawara, Nana Kunii, Takaaki Abe, Eiji Morita, Yoshihisa Tomioka, Pavel Ivanov.
      During viral infection, viral replication perturbs endoplasmic reticulum (ER) homeostasis and triggers the unfolded protein response (UPR). XBP1s, a transcription factor generated by one branch of the UPR, is known to potentiate both innate and adaptive immunity, but its role in antiviral responses remains incompletely understood beyond its ability to augment type I interferon (IFN) mRNA induction. Here, we show that XBP1s positively regulates the RIG-I-like receptors (RLRs), ribonuclease L (RNase L), and protein kinase R (PKR) pathways, indicating that it enhances all three major antiviral response pathways. We further show that RNase L activation rapidly decreases XBP1 mRNA levels in an RNase activity-dependent manner, leading to a prompt reduction in XBP1s expression. Consistent with this, RNase L deletion significantly increased both thapsigargin-mediated XBP1s induction and XBP1s expression following Japan encephalitis virus infection. Poly(I:C)-induced IFNB mRNA expression was significantly enhanced in RNase L-knockout cells. This enhancement was completely abolished by RNase L reconstitution. XBP1 knockdown also significantly attenuated IFNB mRNA expression in RNase L-knockout cells. These findings suggest a negative-feedback loop in which RNase L suppresses XBP1s, thereby fine-tuning antiviral responsiveness during viral infection.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.03.21.713401
  8. Cell Rep. 2026 Apr 01. pii: S2211-1247(26)00256-1. [Epub ahead of print]45(4): 117178
    Synergistic degradation of circular RNAs by RNAseK and lysosome.
    Yuqi Deng, Yuyao Luo, Ruikun Wu, Ping Han, Baolong Wang, Li-Qin Tang, Huaizhi Wang, Ying Zhou, Ge Shan.
      Circular RNAs (circRNAs) are vital in many physiological and pathological events. Compared to the other processes of circRNA metabolism, circRNA degradation is less understood. Through RNAi screening and further characterization, RNAseK and lysosome are identified as circRNA degradation modules in metazoan, and RNase 1 as a lysosomal circRNA endoribonuclease in mammals. RNAseK and lysosome function synergistically, with RNAseK degrading circRNAs outside and lysosome degrading those inside the organelle. Mutations of RNAseK- or lysosome-sensitive sites in in vitro synthesized circRNA reporters lead to higher expression levels, and simultaneous mutations of both sensitive sites result in further increase. Under stress stimuli such as heat shock and ER stress, significantly decreased global circRNA levels are observed in Caenorhabditis elegans. RNAseK deficiency or lysosome inhibition diminishes the decreases in circRNA levels and impedes the induction of stress response, suggesting that circRNA degradation by RNAseK and lysosome plays protective roles in C. elegans stress response.
    Keywords:  CP: cell biology; CP: molecular biology; CircRNA; RNAseK; RNase 1; circRNA degradation; lysosome
    DOI:  https://doi.org/10.1016/j.celrep.2026.117178
  9. Trends Cancer. 2026 Apr 01. pii: S2405-8033(26)00056-7. [Epub ahead of print]
    Unexpected role of the integrated stress response in cancer immune evasion.
    Lucia Borriello, Lorenzo Galluzzi.
      Viral mimicry, i.e., the ability of uninfected cancer cells to emit molecular signals normally associated with infection, is paramount for anticancer immunity. Recent findings from Bossowski et al. indicate that the integrated stress response (a crucial component of cellular responses against infection) can unexpectedly promote immune evasion via an LCN2-driven, macrophage-dependent mechanism.
    Keywords:  ATF4; ER stress response; SLC22A17; T cell exclusion; immunogenic cell death; three Cs
    DOI:  https://doi.org/10.1016/j.trecan.2026.03.001
  10. Cell Death Differ. 2026 Apr 01.
    STING is the scaffold protein for stress granule pre-condensation at the ER.
    Eunchong Eom, Jihyun Kim, Jaehoon Kim, Suk-Jo Kang.
      Stress granules (SGs) are dynamic, membraneless ribonucleoprotein condensates that assemble in response to cellular stress and coordinate diverse cellular stress responses and diseases. Although SG have been reported to associate with the endoplasmic reticulum (ER), how ER-localized stress granule assembly is organized and regulated remains unclear. STING (stimulator of interferon genes) is a central innate immune adaptor that has recently been implicated in diverse non-canonical cellular functions, yet its potential link to SG regulation has not been established. Independent of its canonical functions in innate immune signaling, we identified a novel role of STING as a regulator of SG formation. We found that prior to stress stimulation, STING interacts with key SG core components G3BP1 and UBAP2L via its C-terminal domain (CTD) at the ER, forming a pre-condensation complex that facilitates SG maturation in response to stress. Loss of STING reduces SG formation and increases stress-induced cell death, whereas ER-anchored STING CTD is sufficient to reverse them. Mechanistically, STING enhances basal interactions between G3BP1 and UBAP2L, lowering the threshold for SG maturation upon stress. In addition, STING promotes the pathologic effects of TDP-43 mutations associated with amyotrophic lateral sclerosis. Our findings implicate STING as an ER-resident regulator of SG dynamics that contributes to neurodegenerative pathology, highlighting it as a potential therapeutic target in diseases associated with aberrant SG assembly.
    DOI:  https://doi.org/10.1038/s41418-026-01734-5
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒05 at 16:11.